Evaluation of AT-752, a Double Prodrug of a Guanosine Nucleotide Analog with In Vitro and In Vivo Activity against Dengue and Other Flaviviruses.

Abstract

Every year, millions of people worldwide are infected with dengue virus (DENV), with a significant number developing severe life-threatening disease. There are currently no broadly indicated vaccines or therapeutics available for treatment of DENV infection. Here, we show that AT-281, the free base of AT-752, an orally available double prodrug of a guanosine nucleotide analog, was a potent inhibitor of DENV serotypes 2 and 3 in vitro, requiring concentrations of 0.48 and 0.77 μM, respectively, to inhibit viral replication by 50% (EC50) in Huh-7 cells. AT-281 was also a potent inhibitor of all other flaviviruses tested, with EC50 values ranging from 0.19 to 1.41 μM. Little to no cytotoxicity was observed for AT-281 at concentrations up to 170 μM. After oral administration of AT-752, substantial levels of the active triphosphate metabolite AT-9010 were formed in vivo in peripheral blood mononuclear cells of mice, rats, and monkeys. Furthermore, AT-9010 competed with GTP in RNA template-primer elongation assays with DENV2 RNA polymerase, which is essential for viral replication, with incorporation of AT-9010 resulting in termination of RNA synthesis. In AG129 mice infected with DENV D2Y98P, treatment with AT-752 significantly reduced viremia and morbidity and increased survival. The demonstrated in vitro and in vivo activity of AT-752 suggests that it is a promising compound for the treatment of dengue virus infection and is currently under evaluation in clinical studies.

• Authors: Steven S Good, Ashleigh Shannon, Kai Lin, Adel Moussa, Justin G Julander, Paolo La Colla, Gabriella Collu, Bruno Canard, Jean-Pierre Sommadossi
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 65 Issue 11 Pg. e0098821 (10 18 2021) ISSN: 1098-6596 [Electronic] United States
• PMID: 34424050 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Nucleotides
• Prodrugs
• Guanosine

Topics

• Animals
• Antiviral Agents (pharmacology, therapeutic use)
• Dengue (drug therapy)
• Dengue Virus
• Flavivirus
• Guanosine (pharmacology, therapeutic use)
• Leukocytes, Mononuclear
• Mice
• Nucleotides (therapeutic use)
• Prodrugs (pharmacology, therapeutic use)
• Rats
• Virus Replication